Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:35])([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 93 %

Procedure:
A mixture of 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (440 mg, 0.90 mmol) in ethanol (8 mL), tetrahydrofuran (10 mL) and an aqueous sodium hydroxide solution (10%, 3 mL) was heated at 50° C. for 16 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (290 mg, 92%) which was used in the next step without further purification: LC/MS m/e calcd for C23H26N2O [M+H]+ 347.48, observed 347.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])=[O:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:23]([C:22]3[CH:21]=[C:20]([CH:28]=[CH:27][CH:26]=3)[C:18]([O:17][CH3:16])=[O:19])=[O:24])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (200 mg, 0.81 mmol), 3-(methoxycarbonyl)benzoic acid (145 mg, 0.81 mmol), and N,N-diisopropylethylamine (0.56 mL, 3.22 mmol) in N,N-dimethylformamide (4 mL) was add HBTU (458 mg, 1.21 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (20 mL). This was extracted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) to give 301 mg (>99% yield) of the title compound as yellow syrup.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].Cl>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(SC3CCCCC3)ccc2c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCCCOC(=O)c1nc(C#N)c2cc(SC3CCCCC3)ccc2c1O
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A mixture of 1-Bromo-7-cyclohexylsulfanyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (686 mg, 1.57 mmol) and CuCN (279 mg, 3.13 mmol) in 3.6 mL of NMP was heated in a 130-135° C. oil bath for 3 h. Reaction mixture was diluted with CH2Cl2 (120 mL) and stirred at room temperature overnight. Then 100 mL of 0.5 N HCl aqueous solution was added and the resultant mixture was stirred vigorously for 30 min Two phases were separated and organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was purified by silica gel chromatography, eluting with 5-60% EtOAc/hexanes, to provide the title compound 470 mg (1.22 mmol) in 78% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 12.36 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.50 (t, J=6.8 Hz, 2H), 3.50 (br m, 1H), 2.10 (m, 2H), 1.87-1.39 (m, 12H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1.C[C:22]([C:24]1[CH:29]=CC(F)=C[CH:25]=1)=[O:23].ClC1C=CC(C(F)(F)F)=C[N:33]=1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:22](=[O:23])[CH:24]([CH3:29])[CH3:25])=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:33]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone. To a solution of 4-fluoroacetophenone (13.8 g, 100 mmol) and 2-chloro-5-trifluoromethylpyridine (20.0 g, 110 mmol) in 400 ml of anhydrous THF was added NaH (5.56 g, 220 mmol) (washed with pentane prior to use) in several portions. The reaction was stirred under argon at room temperature for 3 days. The reaction was carefully quenched with H2O (300 ml), followed by addition of diethyl ether (200 ml). The organic layer was separated and extracted with 6N HCl (2×300 ml). The aqueous extracts were cooled to 0° C. and 6N NaOH was added dropwise to adjust the pH of the solution to pH 11-12. The mixture was then extracted with diethyl ether (4×150 ml) and the combined organic layers were then dried over MgSO4. Filtration and concentration furnished 22.4 g (79%) of the title compound as a tautomeric mixture.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C1COCC1>CCOC(C)=O>[C:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
Ethyl bromoacetate (1.70 g, 10.2 mmol), tris-(1-naphthylene)phosphine (379 mg, 0.93 mmol) and tribasic potassium phosphate (10.8 g, 51 mmol) were placed in a flask. The flask was evacuated and back-filled with argon. A solution of 4-acetylphenylboronic acid (2.0 g, 12.2 mmol) in anhyd THF (40 mL) was added to the flask. The reaction was stirred at rt for 16 h. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue was pre-adsorbed on to SiO2 and the product isolated via SiO2 chromatography to yield 616 mg (29%) of ethyl 4-acetyl-phenylacetate. MS 207.1 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC1C=CC(S(O[CH2:22][CH2:23][CH:24]=[C:25]([F:27])[F:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:26][C:25]([F:27])=[CH:24][CH2:23][CH2:22][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)=CCCSc1nc2ccccc2o1
Yield: 120.6 %

Procedure:
2-Mercaptobenzoxazole (4.79 g) was added to a solution of 1,1-difluorobut-1-en-4-yl 4-methylbenzenesulphonate (6.4 g) in acetone (200 cm3) containing potassium carbonate (5.06 g). The mixture was heated to reflux overnight (17 hr) and gc used to confirm that the 1,1-difluorobut-1-en-4-yl 4-methylbenzenesulphonate had been consumed and the product had formed. The reaction mass was allowed to cool and was filtered through a plug of High-Flo filter aid to remove insoluble inorganic material. The solid material was washed with ethyl acetate and the combined organic portions evaporated under reduced pressure to give 7.1 g of a brown oily residue. This material was fractionated by eluting through a bed of silica using hexane/ethyl acetate (40:1 by volume) as solvent to give the required product as a colourless oil (5.4 g, 92% based on the sulphonate); M+ =241;
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:21][S:22][C:23]1[CH:24]=[C:25]([O:31]C)[C:26]([O:29]C)=[N:27][CH:28]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:21][S:22][C:23]1[CH:24]=[C:25]([OH:31])[C:26](=[O:29])[NH:27][CH:28]=1
Reactant: COc1cc(SCc2cc(F)cc(Cl)c2)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2cc(F)cc(Cl)c2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 5-[(3-chloro-5-fluorobenzyl)sulfanyl]-2,3-dimethoxypyridine (Intermediate 13).
Reaction SMILES: C(O[C:6]([NH:8][NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=O)(C)(C)C.Cl.[C:16]([C:19](=CN(C)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)[CH3:17]>C(O)C>[CH:10]1([N:9]2[C:16]([CH3:17])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[N:8]2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(C)(C)OC(=O)NNC1CCCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCC2)c1C
Yield: 76.3 %

Procedure:
To a solution of 1-cyclopentylhydrazine-2-carboxylic acid tert-butyl ester (18.4 g, 92 mmol) in a mixture of ethanol (300 mL) and conc. HCl (7.7 mL, 92 mmol) was added ethyl 2-acetyl-3-(dimethylamino)acrylate (25.5 g, 0.138 mol). The resulting mixture was refluxed for 2 h. The reaction was concentrated in vacuo, dissolved in CH2Cl2 (300 mL), washed with satd NaHCO3, and brine, dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel to give ethyl 1-cyclopentyl-5-methyl-1H-pyrazole-4-carboxylate (15.6 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1 H), 4.61 (m, 1 H), 4.15 (q, J=8 Hz, 2 H), 2.29 (s, 3 H), 2.04-1.97 (m, 2 H), 1.89-1.85 (m, 2 H), 1.78-1.71 (m, 2 H), 1.62-1.59 (m, 2 H), 1.23 (t, J=8 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[C:17]1[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1ccccc1C(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methoxybenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and o-anisoyl chloride in a similar manner as described above to give a pale orange solid (67% yield). 1H-NMR (CDCl3): δ 9.06 (s, 1H), 8.31 (d, 1H), 8.25 (dd, 1H), 7.60 (d, 1H), 7.46 (m, 1H), 7.20 (dd, 1H), 7.17 (dd, 1H), 7.10 (m, 1H), 6.96 (d, 1H), 5.31 (m, 1H), 3.91 (s, 3H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 399 (M−1).
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>CO>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: C[C@H](CCc1ccc(C#CCCCc2ccccc2)s1)C(N)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCc1ccc(C(=O)CCCCc2ccccc2)s1)C(N)O
Temperature: 0 °C
Yield: 82 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol (387 mg, 1.18 mmol) obtained in Example 49 was dissolved in methanol (4 ml), and 6N sulfuric acid (4 ml) was added thereto followed by heating under reflux for 4 hours. The reaction solution was cooled to 0° C. and made alkaline (pH 14) with a 1N aqueous sodium hydroxide solution, and the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (Chromatorex NH (100-200 mesh)) (elution solvent; dichloromethane:methanol=1:0−50:1) to afford (2R)-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol (336 mg, 82% yield). This compound was dissolved in methanol, and oxalic acid (88 mg, 0.97 mmol) was added thereto to precipitate crystals. The crystals were recrystallized from methanol to afford-the title compound (332 mg, 78% yield) as white crystals.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH2:13])=[NH:12])[N:10]=1)(=[O:4])[CH3:3].[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.C([O-])(=O)C.[Na+]>C(O)C>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[NH:13][C:26]([CH3:28])=[C:25]([C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]([C:16]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=3[Cl:14])[N:12]=2)[N:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1nc(C(=N)N)cs1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2csc(NC(C)=O)n2)=NC1c1ccc(F)cc1Cl
Yield: 35.5 %

Procedure:
2 mmol 2-Acetylamino-4-thiazolformamidine hydrochloride, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.31 g of a colorless crystal with mp 220-223° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.01-1.04 (3H, m); 2.13 (3H, s); 2.40-2.42 (3H, d); 3.91-3.97 (2H, m); 5.97 (1H, s); 7.15-7.39 (3H, m); 7.64-7.83 (1H, d); 8.33-8.98 (1H, d); 12.33 (1H, s); MS (EI) 436.0 (M+).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:44][CH2:45][C:46](O)=[O:47])(OC(C)(C)C)=O.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CCN(CC)CC>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:46](=[O:47])[CH2:45][NH2:44])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 in DMF (2.0 ml), Et3N (8.4 μl ) was added, Boc-glycine (21 mg) and WSC.HCl (23 mg) were added at room temperature and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC. A 4 N hydrogen chloride/ethyl acetate solution was further added thereto, and the reaction mixture was stirred for 1 hour, and then the solvent was evaporated. The obtained residue was dissolved in ethyl acetate, washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried, and then the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:26]#[N:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-:30].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]([NH2:27])=[O:30])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
4-(N-Benzyl-N-methylamino)-1-cyano-1,1-diphenylbutane (2 g-see Preparation 2) was dissolved in 90% sulphuric acid (11 ml) and the solution heated at 100° for 3 hours. The solution was allowed to cool to room temperature then poured slowly into water (100 ml). The mixture was made basic (pH 10) by the addition of 10% aqueous sodium carbonate and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to leave the title compound as a colourless foam, yield 1.9 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[C:17]([CH3:22])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>O>[CH3:22][C:17]1[C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:32]4[CH2:33][C@@H:28]5[CH2:34][C@H:31]4[CH2:30][O:29]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:23]([F:26])([F:25])[F:24])=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1noc(C)c1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 56.2 %

Procedure:
200 mg (0.51 mmol) of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg (0.61 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 178 μl (1.28 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=1[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](=[N:31][O:32][CH3:33])[C:26]([N:28]([OH:30])[CH3:29])=[O:27])[C:13]=1[F:34].[C:39](Cl)(=[O:41])[CH3:40].O>O1CCCC1>[C:39]([O:30][N:28]([CH3:29])[C:26](=[O:27])[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:14]1[C:13]([F:34])=[C:12]([O:11][C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]=2[Cl:8])[N:17]=[CH:16][N:15]=1)=[N:31][O:32][CH3:33])(=[O:41])[CH3:40]
Reactant: CON=C(C(=O)N(C)O)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N(C)OC(C)=O)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 g (0.0012 mol) of triethylamine is initially added to a mixture of 0.4 g (0.0009 mol) of 2-(2-{[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy}phenyl)-N-hydroxy-2-(methoxyimino)-N-methylacetamide in 20 ml of tetrahydrofuran, and 0.08 g (0.00099 mol) of acetyl chloride is then added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into 100 ml of water and extracted 3 times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (4:1). This gives 0.18 g (41.1% of theory) of N-(acetyloxy)-2-(2-{[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy} phenyl)-2-(methoxyimino)-N-methylacetamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:5]([O:19][Si](C(C)(C)C)(C)C)[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.[NH:37]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:38]1[C:39](OC)=[O:40].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:39](=[O:40])[CH:38]2[CH2:43][CH2:44][CH2:45][CH2:46][N:37]2[C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reactant: COC(=O)C1CCCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N=C2N(c3ccccc3Br)C(=O)C3CCCCN23)c(O)c1
Yield: 75.2 %

Procedure:
The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (106 mg, 0.25 mmol), diisopropylethylamine (71 μL, 0.28 mmol), methyl pipecolinate hydro chloride (50 mg, 0.28 mmol) and TBAF (0.30 mL, 0.30 mmol) in THF (2.5 mL) and methanol (0.1 mL) to give 80 mg (75%) of 4-[[2-(2-bromophenyl)-1,5,6,7,8,8a-hexahydro-1-oxoimidazo[1,5-a]pyridin-3(2H)-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. MS (EI) m/e 425 (100(M+)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:19][C:20]#[C:21][CH3:22])([CH2:15][C:16]#[C:17][CH3:18])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25]>>[OH:25][NH:24][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH2:19][C:20]#[C:21][CH3:22])[CH2:15][C:16]#[C:17][CH3:18]
Reactant: NO
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 77 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.21 g of the product was isolated. Yield 77%; white solid; mp 161-163° C.; MS:338.1(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.67 (s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J=9.0, 9.0 Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm−1): 3336s, 3245m, 1681s, 1589m, 1493m; Anal. Calc'd for C16H16FNO4S: C, 56.96; H, 4.78; N, 4.15. Found: C, 56.59; H, 4.75; N, 4.04.